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Gastrointestinal (GI) sequelae, such as vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis. These complications result from disease processes (e.g., kidney disease, cystine crystal accumulation in the GI tract) and side effects of treatments (e.g., cysteamine, immunosuppressive therapy). GI involvement can negatively impact patient well-being and jeopardize disease outcomes by compromising drug absorption and patient adherence to the strict treatment regimen required to manage cystinosis. Given improved life expectancy due to advances in kidney transplantation and the transformative impact of cystine-depleting therapy, nephrologists are increasingly focused on addressing extra-renal complications and quality of life in patients with cystinosis. However, there is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. Various publications have examined the prevalence and pathophysiology of selected GI complications in cystinosis, but none have summarized the full picture or provided guidance based on the literature and expert experience. We aim to comprehensively review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines., (© 2024. The Author(s).)

Background: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated., Methods: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016)., Results: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients., Conclusions: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear., (© 2024. The Author(s).)

There is a pressing need for novel pharmacological interventions and drug delivery innovations to attenuate the cigarette smoke-associated oxidative stress and lung disease. We report here on the attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and metabolomics of Wistar rats exposed to cigarette smoke for 28 days. The animals were treated for 15 days with plain cysteamine given orally or cysteamine as nanoemulsion given orally or via inhalation. The study design also included two control groups as follows: rats exposed to cigarette smoke but did not receive a treatment (diseased control group) and rats neither exposed to cigarette smoke nor a treatment (normal control group). The targeted metabolomics using Parallel Reaction Monitoring showed that in the diseased control group, ornithine, nicotinamide, xanthine, hypoxanthine, and caprolactam were increased compared with the normal control group. In addition, (±)8(9)-DiHET, which was initially downregulated in the diseased control group, exhibited a reversal of this trend with cysteamine nanoemulsion given via inhalation. The cysteamine nanoemulsion delivered by inhalation highlighted the importance of the route of drug administration for targeting the lungs. To the best of our knowledge, this is the first work to use ATR-FTIR and metabolomics in Wistar rat lung tissues, suggesting how cysteamine nanoemulsion can potentially reduce cigarette smoke-induced oxidative damage. The metabolites reported herein have potential implications for discovery of novel theranostics and, thus, to cultivate diagnostic and therapeutic innovation for early prevention and treatment of cigarette smoke-associated lung diseases.

Background: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis., Methods: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023., Results: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases., Conclusions: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Melasma is a chronic pigmentary disorder. In this study, an innovative cream combining cysteamine and tranexamic acid (TXA) was assessed., Objective: To evaluate the safety, efficacy, and patient satisfaction of a novel nano-formulated cysteamine and TXA combination cream in treating subjects with epidermal melasma., Methods:   Fifty (50) randomized subjects participated and received cysteamine and TXA combination cream. The cream was applied for 30 minutes daily for a 3-month duration. Treatment effectiveness, safety, patient satisfaction, and adherence were evaluated., Results: A continuous improvement in melasma was observed, with modified Melasma Area and Severity Index (mMASI) scores improving by 40%, 57%, and 63% at 30, 60, and 90 days, respectively. The primary endpoint of a decrease in mMASI scores was met, with 91% of participants experiencing melasma improvement. Patient Satisfaction and Patient Adherence scores indicated satisfaction. Convenience exhibited the strongest correlation with patient adherence.  Conclusion: Nano-formulated cysteamine and TXA combination cream showed significant efficacy in decreasing mMASI score while demonstrating a strong safety profile and patient satisfaction.  J Drugs Dermatol. 2024;23(7):529-537.     doi:10.36849/JDD.7765R1.

Background: Melasma is a chronic dermatosis that impacts the patient's quality of life and can present considerable challenges in terms of effective treatment., Objective: To evaluate the effectiveness, tolerability, and safety of 5% cysteamine combined with 4% nicotinamide in female subjects with melasma., Methods: This single-center, single-arm, prospective, open-label study evaluated patients with melasma using a combination cream of 5% cysteamine and 4% nicotinamide in a progressive regimen (60 min in the first month, 120 min in the second month, and 180 min in the third month)., Results: Overall, 35 treated subjects exhibited reduced modified Melasma Area and Severity Index (mMASI) (p < 0.001) and decreased MelasQoL scores (p < 0.001), accompanied by improved brightness, luminosity, homogeneity, and spot intensity (p < 0.001). Photographic and colorimetric analysis revealed smaller spots and improved homogeneity., Limitations: Adherence to progressive daily treatment could not be evaluated long-term., Conclusion: A combination cream comprising 5% cysteamine and 4% nicotinamide was effective, tolerable, and safe for treating melasma., (© 2024 Libbs Farmaceutica Ltda. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

This study investigated the impact of different levels of coated cysteamine hydrochloride (CSH) supplementation on ruminal fermentation, nutrient digestibility, and blood metabolites in Charolais cross bulls. Twelve bulls were allotted to three feeding treatments in a replicated 3 × 3 Latin square design: 0% CSH (control), 0.5% CSH, and 1.0% CSH in concentrate. Animals were fed concentrate at 1.5% of body weight. Dry matter intake (DMI) and DMI as a percentage of body weight showed no significant differences among treatments (p > 0.10). Nutrient digestibility was consistent across treatments, except for a slight decrease in NDF digestibility with 1% CSH (p = 0.07). Ruminal pH, ammonia nitrogen, volatile fatty acid (VFA) proportions, and total VFA concentration were similar among treatments (p > 0.05). Total bacteria, fungal zoospores, and protozoa populations in the rumen did not vary significantly (p > 0.05). Blood glucose and triglyceride concentrations remained stable (p > 0.05), while blood urea nitrogen (BUN) levels were higher in CSH-supplemented groups (p < 0.05). In conclusion, incorporating CSH levels ranging from 0.5% to 1.0% into the diet did not adversely affect feed intake, ruminal fermentation, or microbial populations. Additionally, 1.0% CSH improved BUN concentration in growing Charolais cross bulls., (© 2024 Japanese Society of Animal Science.)

This study was aimed at evaluating the efficacy of Tranexamic Acid (TA) mesotherapy versus cysteamine 5% cream in the treatment of melasma. This single-blind, randomized clinical trial was conducted among 54 subjects between 2018 and 2019. Cysteamine 5% cream group was instructed to apply the cream on the melasma lesions 30 min before bed for 4 consecutive months. Conversely, 0.05 mL (4 mg/mL) TA mesotherapy was performed by a physician every 4 weeks until 2 months. The severity of melasma was evaluated using both Dermacatch® device and the modified Melasma Area Severity Index (mMASI). The most remarkable improvement rate was observed in the TA group at the third visit based on mMASI and Dermacatch® values at 47% and 15% in turn. The mMASI scores were substantially improved in both groups at the second visit (cysteamine vs TA 8.48 ± 2.34 and 7.03 ± 3.19; P = 0.359) and third visit (cysteamine vs TA 6.32 ± 2.11 and 5.52 ± 2.55; P = 0.952) as compared to baseline (cysteamine vs TA: 11.68 ± 2.70 and 10.43 ± 2.69). Dermacatch® values were significantly declined at the second and third visits (cysteamine vs TA 42.54 ± 12.84 and 38.75 ± 9.80, P = 0.365; 40.74 ± 12.61 and 36.17 ± 10.3, P = 0.123, respectively) compared with baseline (cysteamine vs TA 45.76 ± 13.41 and 42.41 ± 10.48), although the improvement rates between two groups were not significantly different. Findings suggest that none of the cysteamine and TA mesotherapy treatments measured by both mMASI and Dermacatch® methods have substantial advantages over the other; however, complications are less in the cysteamine than the TA mesotherapy group., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aims: Cystinosis is a rare, autosomal recessive disorder causing defective transport of cystine out of lysosomes. Cystadrops (0.55% cysteamine hydrochloride in viscous solution) has been used on a named-patient basis to treat the accumulation of cystine crystals in the cornea in patients with cystinosis., Methods: Retrospective analysis of the Temporary Authorisation for Use cohort of 130 patients who received Cystadrops between 2013 and 2017 in France., Results: Patients received an average dosage of 3.3 (±0.94) instillations per eye per day. Over the duration of follow-up, of up to 45 months, patients maintained visual acuity scores of 0.0, which approximated normal. Corneal cystine crystal scores tended to decrease over time, stabilising after around 27 months between 1.22 and 1.87. Photophobia decreased within 3 months, stabilising on scores of around 1.5 and 1.7. 47 non-serious adverse reactions were reported, which were generally transient irritation, stinging or blurred vision. Four serious adverse events were reported, including keratitis and corneal ulcer, but these may have been caused by the underlying disease., Conclusion: This large safety cohort confirms the efficacy, safety and tolerability of Cystadrops in real-world clinical practice., Competing Interests: Competing interests: HL has received speaker honoraria from Recordati Rare Diseases, HL has received research funding from October-1 and CHOC clinical trials honoraria. AL has received speaker honoraria from Recordati Rare Diseases, and research funding from October-1 honoraria. CB has received honoraria from Orphan Europe. CP and VG are both employees of Recordati Rare Diseases., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although it is well-recognized that antioxidant nano-encapsulation has many benefits such as minimizing side effects (e.g., high-dose toxicity), the most attention was paid to the hydrophobic antioxidant not hydrophilic. In this regard, we sought to compare two hydrophilic model nanocarriers to deliver the optimal dose of cystamine (Cys) into the in vitro matured oocyte and the first cleavage stages until morula-compact stage embryonic cells. The formation of Cys-loaded solid self-emulsifying lipid (Cys + SLN) and Cys-loaded chitosan shell (Cys-CS-NC) were confirmed by FT-IR and UV-Vis spectrophotometry, dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) technologies. In two experiments, the oocytes/presumptive zygotes were cultured under various concentrations of Cys-SLN and Cys-CS-NC. The results of nuclear staining (aceto-orcein and Hoechst 33342), H2DCFDA fluorescent staining, chemiluminescence test, and quantitative reverse transcription-PCR (qRT-PCR) technique as in vitro toxicity studies demonstrated that adding the lowest dose of Cys-encapsulated in both nanocarriers [Cys-SLN (5 μM) and Cys-CS-NC (10 μM)] to maturation or culture medium could accumulate a strong anti-oxidative effect in oocyte/embryo by controlled release and enhanced intracellular penetration of Cys. In comparison, Cys-SLN (5 μM) is more effective than Cys-CS-NC (10 μM) groups to improve the expression of antioxidant genes (SOD, CAT, GPx) or anti-apoptotic (BCL-2) gene and decreased apoptosis (BAX and caspase-3) or intra-/extracellular ROS levels. In a nutshell, both nanocarriers (CS-NC or SLN) can deliver the lowest dose of Cys into the oocyte/embryo, thus encouraging a better expansion of antioxidant genes and enhancing the development of in vitro oocyte/embryo.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon ® (immediate-release) and Procysbi ® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM ® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower C max and longer T max compared to Cystagon ® and Procysbi ® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon ® intake. Population PK simulations showed a favourable PK profile based on C max and C trough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18)., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Purpose: To evaluate safety and efficacy of topical cysteamine ophthalmic solution for corneal cystinosis., Methods: Seven databases were searched (PubMed, OVID, EMBASE, Web of Science, Cochrane Central, Google Scholar, and ClinicalTrials.gov) for relevant studies, using appropriate keywords. Comparative observational studies and randomized controlled trials comparing cysteamine with control or other formulations for treatment of corneal or ophthalmic cystinosis were included. Outcome measurements were improvement or response to therapy, change in corneal cystine crystal score (CCCS), in vivo confocal microscopy score (IVCM), cystine crystal depth, contrast sensitivity (CS), photophobia score, and safety., Design: Systematic review and meta-analysis., Results: Seven studies were included. Compared to placebo and control, the cysteamine arm was better in terms of improvements and responses to therapy (2 studies showed a risk ratio [RR] of 16; 95% confidence interval [CI]: 2.30-111.37) and crystal density score (1 study showed a mean difference [MD] of -0.80; 95% CI: -1.56 to -0.04). No significant differences were observed in terms of improvement in CS (1 study showed an RR of 7.00; 95% CI: 0.47-103.27). Compared to cystamine, cysteamine showed benefits in terms of crystal density score (MD -0.94; 95% CI: -1.64 to -0.24). Compared to a newer formulation, the standard formulation (cysteamine [Cystaran]; 0.55% cysteamine hydrochloride + benzalkonium chloride 0.01%) performed better in terms of decreasing CCCS. Another newer, viscous formulation, Cystadrops, performed better than the standard formulation in terms of change in CCCS, IVCM score, corneal crystal depth, and photophobia score; however, local adverse effects and blurring were higher in the group receiving Cystadrops., Conclusions: Conventional cysteamine (0.1% to 0.3%) performed better than placebo (control) in terms of response to therapy. In terms of decreasing corneal cystine density, cysteamine (0.55%) was better than cystamine (0.55%), and the viscous Cystadrops (0.55%) was better than the standard formulation (0.1%)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Predictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial., Approach and Results: This study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52 weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P < 0.0001) retained baseline and change in GGT (area under the receiver operating characteristic [AUROC], 0.79; 95% confidence interval [CI], 0.71-0.87). For borderline zone 1 NASH, the model (P = 0.0004) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). For fibrosis, the model (P < 0.001) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). Additional clinical parameters were added to the models using Akaike's information criterion selection, and significantly boosted performance: improvement in histology with AUROC of 0.89 (95% CI, 0.82-0.95), borderline zone 1 NASH with AUROC of 0.91 (95% CI, 0.83-0.99), and fibrosis with AUROC of 0.89 (95% CI, 0.82-0.94). Models were validated using data from the TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial., Conclusions: In children with NAFLD, dynamic changes in serum ALT and GGT are associated with change in liver histology and appear to be powerful indicators of histological response., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints?, Methods and Findings: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049., Conclusion: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures., Clinical Trial Registration: NCT03000348; www.clinicaltrials.gov., Competing Interests: The authors have read the journal's policy and have the following competing interests: Deborah A O’Neil (DO) is the CEO, CSO, and shareholder of the trial sponsor NovaBiotics Ltd. Douglas J Fraser-Pitt (DFP) is a Principal Scientist and salaried employee of the trial sponsor NovaBiotics Ltd. Emma Lovie (EL) is a research scientist and Jennifer Robertson (JR) is a laboratory manager/research scientist; Both are salaried employees of the trial sponsor NovaBiotics Ltd. Graham Devereux (GD) received support from NovaBiotics Ltd to attend the 2018 NACFC. Danielle Wrolstad (DW) reports personal fees through her employer (Precision Medicine Group) from NovaBiotics Ltd, during the study. Rose Franco (RF), Stephen J Bourke (SB), Benjamin T Kopp (BK) and Ryan Dougherty (RD) report grant from NovaBiotics Ltd during the conduct of the study. SB & BK report grants from Vertex outside the submitted work. DFP and DO are authors of patent; WO2016198842A1, IL256162D0 - An amino thiol for use in the treatment of an infection caused by the bacterium mycobacterium spp. DO is also author of the following patents; US9364491B2 (and other territories) - Antimicrobial compositions with cysteamine/A composition comprising an antibiotic and a dispersant; WO2016046524A1 - Use of cysteamine in treating infections caused by yeasts/moulds; US9782423B2 (and other territories) - Antibiotic compositions comprising an antibiotic agent and cysteamine; US9339525B2 (and other territories) - Inhibition of biofilm organisms; and US20190175501A1 pending (and other territories) - Microparticles comprising a sulphur-containing compound. (JR, EL, DFP, and DO) are involved in the development of cysteamine bitartrate as a therapy for cystic fibrosis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 μmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The eicosapentaenoic acid (EPA) is an n-3 polyunsaturated fatty acid (PUFA) present in the lipid composition of bovine oocytes. Little is known about the importance of EPA in bovine oocyte maturation and embryo development in vitro. Although previous work suggest that n-3 PUFAs may inhibit oocyte maturation, the available data are inconsistent. In this study, we evaluated the effect of EPA (1, 10, 100 nM) during in vitro maturation (IVM) of bovine oocytes, alone and in combination with vitamin E (VE) or cysteamine (CYS). EPA treatment in IVM decreased oocyte lipid content and affected lipid droplets pattern (P < 0.05). EPA 100 nM reduced oocytes maturation rate (P < 0.05), without affecting cumulus expansion. At the concentrations tested, EPA did not modify embryo development. However, the addition of antioxidants during IVM reduced the levels of reactive oxygen species in the culture system by increasing intracellular glutathione content (P < 0.05). Besides, the combination of EPA with VE or CYS reduced the percentages of MI oocytes after 24 h of IVM (P < 0.05). EPA reduced oocyte lipid content without any detrimental for embryo development., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required. In this article, we provide an overview of a successful collaboration in nephropathic cystinosis (NC), focusing on what was the key of success, the interactions between academics, the pharmaceutical company and patients organizations. NC is considered as a very rare disease. In 2010, a new formulation of cysteamine, the only available treatment to improve renal outcome of the disease, was proposed by a small American company. Studies were implemented in France under the coordination of an expert of the disease and the clinical investigation center of Lyon. The collaboration resulted in a good recruitment and retention of the patients in the study and most of all in the availability of the new formulation in France. Patients could have facilitated the research by being involved in the early stages of the studies. Involving patients and public early in the process is particularly important in rare diseases as the patient is a great source of knowledge and has his own expectations. Priorities of research, design, conduct and reporting of clinical trials can be defined in collaboration with adults but also with young patients or public, the first concerned in rare diseases. This concept is still to be developed and improved especially with paediatric patients., (Copyright © 2020. Published by Elsevier Masson SAS.)

Little is known about the long-term progression of adult nephropathic cystinosis patients. Our objective was to study central nervous system complications in cystinosis patients in the era of early cysteamine treatment, using advanced neuroimaging techniques. Neurological examination and multimodal brain 3 Tesla MRI were performed in 21 adult cystinosis patients, including 18 infantile cystinosis patients, 20 controls matched for age and renal function, and 12 healthy controls. Differences in gray matter volume and rest cerebral blood flow (CBF) using arterial spin labeling sequence were investigated using whole-brain voxel-based approach. Median age was 33.8 years (18.7-65.8). Seven patients (38.9%) presented with at least one central nervous system clinical abnormality: two (11.1%) with seizures, three (16.7%) with memory defects, five (27.8%) with cognitive defect, and one (5.5%) with stroke-like episode. These patients had a worse compliance to treatment (compliance score 2 vs 1, P = .03) and received a lower median cysteamine dose (0.9 g/day vs 2.1 g/day, P = .02). Among patients with infantile cystinosis, 13 (72.2%) showed cortical atrophy, which was absent in controls, but it was not correlated with symptoms. Cystinosis patients showed a significant gray matter decrease in the middle frontal gyrus compared with healthy controls and a significant negative correlation between the cystine blood level and rest CBF was observed in the right superior frontal gyrus, a region associated with executive function. Compliance to cysteamine treatment is a major concern in these adult patients and could have an impact on the development of neurological and cognitive complications., (© 2019 SSIEM.)

Background: Cysteamine was coated to cover its odor and maintain the stability. However, coated cysteamine (CC) has not been clearly evaluated for its effects on the gastrointestinal mucosa status. We hypothesize that the appropriate CC supplementation in diet impacts the stomach and intestinal mucosa variously through regulating the morphology, apoptosis, and oxidative stress status in model of pigs., Results: The results showed that villus height increased (P < 0.05), and crypt depth decreased (P < 0.05) in the ileum when pigs were fed the diet with low cysteamine (LCS) compared with the control diet. The ileal lesion score in the LCS group was significantly (P < 0.01) lower than that in the control group, while the gastric lesion score in the CC group was significantly (P < 0.01) higher compared with that of the control group. It also showed that the activities of total superoxide dismutase (T-SOD) and diamine oxidase (DAO) were upregulated (P < 0.05) in the LCS group. In addition, Bax and caspase 3 immunore-activity increased (P < 0.01), and Bcl-2 immunoreactivity decreased (P < 0.01) in the gastric mucosa of pigs fed the diet with high cysteamine (HCS). The Bax and caspase 3 immunoreactivity decreased (P < 0.01), and Bcl-2 immunoreactivity increased (P < 0.01) in ileum mucosa of pigs fed the HCS diet., Conclusions: Although moderate dietary coated cysteamine showed positive effects on GI mucosal morphology, apoptosis, and oxidative stress status, the excess coated cysteamine may cause apoptosis leading to GI damage in pigs.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Cystinosis is a rare autosomal-recessive lysosomal storage disease with high morbidity and mortality. It is caused by mutations in the CTNS gene that encodes the cystine transporter, cystinosin, which leads to lysosomal cystine accumulation. Patients with infantile nephropathic cystinosis, the most common and most severe clinical form of cystinosis, commonly present with renal Fanconi syndrome by 6-12 months of age, and without specific treatment, almost all will develop end-stage renal disease (ESRD) by 10-12 years of age. Early corneal cystine crystal deposition is a hallmark of the disease. Cystinosis also presents with gastrointestinal symptoms (e.g., vomiting, decreased appetite, and feeding difficulties) and severe growth retardation and may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles, bone marrow, liver, nervous system, lungs, and bones. Cystine-depleting therapy with cysteamine orally is the only specific targeted therapy available for managing cystinosis and needs to be combined with cysteamine eye drops for corneal disease involvement. In patients with early treatment initiation and good compliance to therapy, long-term cysteamine treatment delays progression to ESRD, significantly improves growth, decreases the frequency and severity of extrarenal complications, and is associated with extended life expectancy. Therefore, early diagnosis of cystinosis and adequate life-long treatment with cysteamine are essential for preventing end-organ damage and improving the overall prognosis in these patients.

Cystinosis is a genetic disorder that leads to the formation of cystine crystals in many organs in the body including cornea. Ocular manifestation of this disease is treated by eye drops of cysteamine which can easily oxidize into its disulfide cystamine. The rapid oxidation limits the shelf life as well the duration during which the drug can be used after opening the eye drop bottle. We evaluate two approaches of preventing the oxidation of cysteamine with the goal of increasing the time of use after opening the bottle to one month. The first approach integrates antioxidants such as catalase enzyme and vitamins C and E into the aqueous solution. Results show that catalase is the most effective additive as it decreases the oxidation rate by 58%, which on its own is not sufficient to reach targeted one month stability. The second approach focuses on incorporating diffusion barriers to prevent oxygen from reaching the cysteamine solution. This was accomplished by two methods: formulation of a hydrophobic layer which floats on the surface of the aqueous solution and integration of OMAC® oxygen-resistant material into the eye drop bottle. Both methods delay the onset of cysteamine degradation and decrease the rate of degradation. In particular, an eye drop bottle with three layers of OMAC® has less than 10% degradation after one month of opening the bottle and withdrawing a drop each day. By integrating all three methods, we designed a system where >90% of cysteamine remains in the active form for 70 days after opening the bottle. In addition, we examine the use of OMAC® as heat-sealed pouches for storage of cysteamine eye drop bottles during packaging to eliminate the need for the current approach of freezing the formulation during shipping. The results show that such heat-sealed pouches would keep cysteamine stable for over one year at ambient conditions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aimed to investigate the effect of cysteamine hydrochloride (CSH) supplementation on the growth performance, opportunistic bacteria and enterotoxic markers, visceral lesions, glutathione turnover, and inflammatory factors of broilers fed diets contaminated with aflatoxin B1 (AFB1). One-day-old Arbor Acres broilers (n = 480) were randomly allocated to 4 treatments with 6 replicates of 20 chicks each for a 2 × 2 design with CSH (0 or 200 mg/kg) and AFB1 (0 or 40 μg/kg). The trial lasted for 42 d. Results showed that AFB1 negatively affected (P < 0.05) growth performance, opportunistic bacteria and enterotoxic markers, intestinal lesions, glutathione turnover, and inflammatory factors. The CSH increased (P < 0.05) feed intake and body weight gain. The enterotoxic status was relieved in the CSH treatments by reducing (P < 0.05) the populations of gut Escherichia coli, Gram-negative bacteria, serum diamine oxidase, and intestinal lesions. The CSH also increased (P < 0.05) serum reduced glutathione, glutathione s-transferases, and glutathione reductase, and decreased (P < 0.05) the mRNA levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β. Significant interactions (P < 0.05) were found on Gram-negative bacteria, diamine oxidase, and glutathione s-transferases. The results suggest that the CSH can improve glutathione turnover and reduce the risk of enterotoxic disease induced by AFB1 in broilers.

Background: Cysteamine bitartrate delayed-release (DR) capsule (Procysbi ® ) is approved for treatment of nephropathic cystinosis in the USA, Canada, and the EU. The capsules contain cysteamine bitartrate beads that are enteric coated with acid-resistant Eudragit L 30 D-55, preventing drug release in the acidic stomach environment while allowing dissolution of the beads in the more alkaline environment of the small intestine. Patients who have difficulty swallowing capsules can open capsules, sprinkle beads onto 4 ounces of a suitable food or liquid, gently mix, and consume the entire content within 30 minutes. Foods found to be suitable for administration, and described in the Procysbi US labeling, include fruit juices (except grapefruit juice), applesauce, and berry jelly; there are minor variations in the foods and liquids recommended by regulatory authorities in other countries. This study aimed to assess the stability of enteric-coated beads exposed to additional foods at different conditions to expand the list of suitable foods for drug administration., Methods: For each test condition, beads from eight opened 75 mg cysteamine bitartrate DR capsules were gently mixed with test food and maintained at a prespecified temperature and duration; remaining undissolved beads were then recovered from the food. The recovered beads were split into two portions: one assayed for remaining drug content and the other subjected to dissolution testing to assess the effect on the drug-release profile., Results: The results show that bead integrity was maintained when mixed with foods at pH values <5.5 at all time points when refrigerated (2°C-8°C) and at room (20°C-22°C) and lukewarm (37°C-41°C) temperatures. Bead integrity was not maintained when mixed with foods at pH values of ≥5.5 at room temperature., Conclusion: The results from this in vitro dissolution study help in identifying additional foods that may be used for the administration of cysteamine bitartrate DR beads from opened capsules using the sprinkle method., Competing Interests: Disclosure At the time this study was conducted, N Pavloff, TA Hauser, SL Isbell, B Cadieux, and M Johnson were full-time employees of Horizon Pharma USA, Inc. C Williams is a full-time employee of Alcami Corporation. The authors report no other conflicts of interest in this work.

This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.

Introduction: Cystinosis is a rare, metabolic, autosomal recessive, genetic lysosomal storage disorder characterized by an accumulation of cystine in various organs and tissues. Cysteamine bitartrate (CB) is a cystine-depleting aminothiol agent approved in the United States and Europe in immediate-release and delayed-release (DR) formulations for the treatment of nephropathic cystinosis in children and adults. It is recommended that CBDR be administered with fruit juice (except grapefruit juice) for maximum absorption. Omeprazole is a proton pump inhibitor that inhibits gastric acid secretion and, theoretically, may cause the premature release of cysteamine by increasing intragastric pH, thereby affecting the PK of CBDR., Methods: This open-label, three-period, randomized study in healthy adult subjects was designed primarily to compare the pharmacokinetics of CBDR capsules after a single oral dose administered with orange juice, water, or multiple oral doses of omeprazole with water at steady state. A total of 32 subjects were randomly assigned to receive study agents in one of two treatment sequences., Results: All subjects completed the study and baseline characteristics of the overall population and the two treatment sequence populations were similar. Peak mean plasma cysteamine concentrations following co-administration of CBDR capsules with orange juice (1892 ng/mL) were higher compared with co-administration with water (1663 ng/mL) or omeprazole 20 mg and water (1712 ng/mL). Mean time to peak plasma concentration was shorter with omeprazole co-administration (2.5 h) compared with orange juice (3.5 h) or water (3.0 h). Statistical comparisons between treatment groups indicated that exposure as assessed by AUC 0-t , AUC 0-∞ , and C max were all within the 80-125% bioequivalence ranges for all comparisons. All treatments were generally well tolerated., Conclusion: Overall, the pharmacokinetics of cysteamine bitartrate DR capsules are not significantly impacted by co-administration with orange juice, water only, or omeprazole (with water)., Funding: Horizon Pharma, Inc.

Background: Current options to treat clinical relapse in inflammatory central nervous system (CNS) conditions such as cerebral ischemia-reperfusion injury are limited, and agents that are more effective are required. Disruption of the blood-brain barrier is an early feature of lesion formation that correlates with clinical exacerbation and facilitates the entry of inflammatory medium and inflammatory cells. Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring anti-inflammatory antagonist of the interleukin-1 (IL-1) family. The broad-spectrum anti-inflammatory effects of IL-1RA have been investigated against various forms of neuroinflammation. However, the effect of IL-1RA on blood-brain barrier disruption following ischemia-reperfusion has not been reported., Methods: In this study, we investigated the effects of IL-1RA and a novel protein (IL-1RA-PEP) that was fused to IL-1RA with a cell penetrating peptide, on blood-brain barrier integrity, in male rats subjected to transient middle cerebral artery occlusion., Results: After intravenous administration, IL-1RA-PEP (50 mg/kg) penetrated cerebral tissues more effectively than IL-1RA. Moreover, it preserved blood-brain barrier integrity, attenuated changes in expression and localization of tight junction proteins and matrix metalloproteinases, and enhanced angiogenesis in ischemic brain tissue. Further study suggested that the effects of IL-1RA-PEP on preserving blood-brain barrier integrity might be closely correlated with the p65/NF-κB pathway, as evidenced by the effects of the inhibitor JSH-23., Conclusions: Collectively, our results demonstrated that IL-1RA-PEP could effectively penetrate the brain of rats with middle cerebral artery occlusion and ameliorate blood-brain barrier disruption. This finding might represent its novel therapeutic potential in the treatment of the cerebral ischemia-reperfusion injury.

Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its  administration by the topical ocular route. The aim of the present study is to  determine the stability of an ophthalmic hydrogel of cysteamine, which can be  potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical  and chemical parameters were evaluated: osmolality, pH and  cysteamine concentration, which has been measured by a method of ultra  performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS).  Descriptive assays were also performed, such as transparency measurement and  microbiological assays in order to verify its sterility. The obtained results  allow us to conclude that the cysteamine hydrogel is stable during 30 days,  being recommendable its preservation in refrigerated conditions., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Cysteamine (an aminothiol), which is derived from coenzyme A degradation and metabolized into taurine, has beneficial effects against cystinosis and neurodegenerative diseases; however, its role in diabetic complications is unknown. Thus, we sought to determine the preventive effect of cysteamine against hyperglycemia-induced vascular leakage in the retinas of diabetic mice. Cysteamine and ethanolamine, the sulfhydryl group-free cysteamine analogue, inhibited vascular endothelial growth factor (VEGF)-induced stress fiber formation and vascular endothelial (VE)-cadherin disruption in endothelial cells, which play a critical role in modulating endothelial permeability. Intravitreal injection of the amine compounds prevented hyperglycemia-induced vascular leakage in the retinas of streptozotocin-induced diabetic mice. We then investigated the potential roles of reactive oxygen species (ROS) and transglutaminase (TGase) in the cysteamine prevention of VEGF-induced vascular leakage. Cysteamine, but not ethanolamine, inhibited VEGF-induced ROS generation in endothelial cells and diabetic retinas. In contrast, VEGF-induced TGase activation was prevented by both cysteamine and ethanolamine. Our findings suggest that cysteamine protects against vascular leakage through inhibiting VEGF-induced TGase activation rather than ROS generation in diabetic retinas., (© 2017 Society for Endocrinology.)

Purpose: The aim of this study is to evaluate the efficacy of topical cysteamine 0.55% eye drops in the treatment of corneal cystine crystal deposits in patients with nephropathic cystinosis., Methods: Thirty-two patients with nephropathic cystinosis were prospectively included in the study. Patients with corneal cystinosis were treated with topical cysteamine 0.55% eye drops. They were examined before treatment, on each monthly visit and after treatment at the last follow-up. Photophobia was classified as grade 0 (none) for no photophobia, grade 1 (mild) for photophobia in bright light, grade 2 (moderate) for photophobia in room light and grade 3 (severe) for photophobia in dim light. Corneal cystine crystals were graded as grade 0=none, grade 1=1-10 crystals/mm 2 , grade 2=11-50 crystals/mm 2 , grade 3=more than 50 crystals/mm 2 . The main outcome measure was evaluation of photophobia and resolution of corneal cystine crystals., Results: There were 13 male and 19 female patients. The mean age was 8 years with an age range of 8 months to 19 years. The mean follow-up period was 4.1 years with a range of 2-8 years. Improvement of photophobia was not clinically significant in symptomatic patients. Patients displayed statistically significant worsening of corneal cystine deposits during the follow-up period., Conclusions: This study has shown that topical 0.55% cysteamine eye drops may have limited effects in decreasing the corneal cystine deposits in patients with severe forms of nephropathic cystinosis., Trial Registration Number: NCT02766855, Results., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [64Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [225Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups (p < 0.05). GBM tissue extracted from mice treated with [225Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [225Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.

Background: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease., Methods: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo., Results: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated., Conclusions: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Purpose: The purpose of this study was to evaluate the efficacy of new viscous cysteamine hydrochloride (CH) eye drops (vCH 0.55%) compared with standard CH 0.10% drops treatment., Methods: This was an open-label, phase III, randomized, two-arm multicenter trial conducted at two centers in France. Cystinosis patients ≥2 years old were randomized 1:1 to receive eye drops, four times per day for 90 days in both eyes. We compared the superiority in reducing corneal cystine crystal density as assessed by in vivo confocal microscopy (IVCM). We also evaluated photophobia, corneal cystine crystal scores (CCCSs), and cystine crystal depth measured by optical coherence tomography. Safety objectives were to assess adverse events (AEs), local adverse drug reactions, and ocular safety parameters., Results: We included 15 patients with vCH 0.55% and 16 patients with CH 0.10% drops for 90 days. The mean absolute change in IVCM total score at day 90 in the vCH 0.55% drops group (-4.6 ± 3.1) was significantly greater than and superior to the mean absolute change in the CH 0.10% drops group (-0.46 ± 3.38; P < 0.0001). Photophobia, CCCS, and corneal cystine crystal depth were significantly more improved in the vCH 0.55% drops group than in the CH 0.10% group. The most frequent local adverse drug reactions in both groups were stinging, burning, redness, and blurred vision., Conclusions: vCH 0.55% was effective in reducing corneal cystine crystal density and superior to treatment with CH 0.10% drops, which offer advantages over hospital pharmacy formulations and is a more preferable and convenient treatment option.

This study aimed to evaluate the effects of cysteamine supplementation on the expression of jejunal amino acid and peptide transporters and intestinal health in finishing pigs. Sixty barrows were allocated into two experimental diets consisting of a basal control diet supplemented with 0 or 142 mg/kg cysteamine. After 41 days, 10 pigs per treatment were slaughtered. The results showed that cysteamine supplementation increased the apparent digestibility of crude protein (CP) (P < 0.05) and the trypsin activity in jejunal digesta (P < 0.01). Cysteamine supplementation also increased the messenger RNA abundance of SLC7A7, SLC7A9 and SLC15A1, occludin, claudin-1 and zonula occludens protein-1 (P < 0.001) in the jejunum mucosa. Increased glutathione content (P < 0.01) and glutathione peroxidase activity (P < 0.05) and decreased malondialdehyde content (P < 0.01) were observed in pigs receiving cysteamine. Additionally, cysteamine supplementation increased the concentrations of secretory immunoglobulin A (IgA) (P < 0.05), IgM (P < 0.001) and IgG (P < 0.001) in the jejunal mucosa. It is concluded that cysteamine supplementation could influence protein digestion and absorption via increasing trypsin activity, enhancing the digestibility of CP, and promoting the expression of jejunal amino acid and peptide transporters. Moreover, cysteamine improved intestinal integrity, antioxidant capacity and immune function in the jejunum, which were beneficial for intestinal health., (© 2016 Japanese Society of Animal Science.)

Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

Background: Nephropathic cystinosis is a rare lysosomal storage disease which is characterized by the accumulation of free cystine in lysosomes and subsequent intracellular crystal formation of cystine throughout the body. If not treated with cysteamine, a cystine-depleting agent, end-stage renal disease will develop early, followed by multiple organ failure as the disease progresses. The established cysteamine formulation requires a strict dosing regimen at 6-h intervals. An extended release (ER) twice-daily formulation has recently been developed. The aim of our study was to evaluate the implementation and outcomes of this option in routine care., Methods: All pediatric cystinosis patients' records in Hannover Medical School were screened, and data on cysteamine therapy, tolerability, dosing, estimated glomerular filtration rates (eGFR), white blood cell cystine levels, and proton pump inhibitor (PPI) use were extracted for the period January 2014 to January 2016., Results: The median age of the 12 patients enrolled in the study was 12.5 (range 1-18) years. At the end of the study period ten of these patients received ER-cysteamine. There were no additional side effects. Halitosis/bad breath was often subjectively judged as improved or eliminated, and PPI use could be stopped in one of three patients. The main reasons for switching to the ER formulation were difficult night-time administration and uncontrolled disease. Mean eGFR values remained stable with a median of 67 ml/min/1.73 m 2 before and after the transition. White blood cell (WBC) cystine values remained low after the switch (1 nmol/mg protein before and after transition; p = 0.64)., Conclusions: In this single-center cohort, the switch from IR- to ER-cysteamine was safe and effective over the short term and provided advantages in terms of frequency of administration and less halitosis/bad breath. The long-term benefit of this option needs to be evaluated in future studies.

Background & Aims: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD., Methods: We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis., Results: There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005)., Conclusions: In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The production of reactive oxygen species (ROS) is a normal process that occurs in the cellular mitochondrial respiratory chain. However, an increase in ROS levels during in vitro production of bovine embryos induces oxidative stress, leading to failed embryonic development. Therefore, we investigated whether supplementation of IVM medium with intracellular (cysteine and cysteamine; C + C) and/or extracellular (catalase; CAT) antioxidants improves the culture system, affects the mitochondrial membrane potential, affects the intracellular levels of ROS and glutathione (GSH) in the bovine oocytes at the end of maturation, and thereby affects the subsequent embryonic development. At the end of IVM, the metaphase II rates were unaffected by the treatments (76.7 ± 1.7% to 80.6 ± 5.2%; P > 0.05). The intracellular ROS levels, expressed in arbitrary fluorescence units, found in the oocytes treated with intracellular antioxidants (C + C and C + C + CAT groups; 1.06, averaged) were as low as those observed in immature oocytes (0 hour: 1.00 ± 0.12). Among mature oocytes, higher (P < 0.05) ROS levels were found in the control group (1.91 ± 0.10) when compared to the ROS levels found in oocytes treated with antioxidants. Intracellular GSH levels in all groups were lower (0.17 ± 0.09 to 0.51 ± 0.05; P < 0.05) than those in immature oocytes (1.00 ± 0.08), although GSH levels in the C + C group (0.51 ± 0.05) were greater (P < 0.05) than in the control, CAT, and C + C + CAT groups (0.23; averaged). The mitochondrial membrane potential in all groups was improved (1.6; averaged; P < 0.05) compared to the membrane potential observed in the immature oocytes (1.00 ± 0.05), with the exception of the C + C group (0.94 ± 0.03). There was no effect (P > 0.05) of antioxidant supplementation on embryonic development to the blastocyst stage (36.1%; averaged); however, there was an increased tendency (P = 0.0689) to obtain a higher blastocyst rate for the C + C + CAT group (47.5 ± 5.6%) compared to the control group (29.9 ± 4.8%). In conclusion, despite improvements in specific parameters of cytoplasmic maturation, the addition of intracellular and/or extracellular antioxidants during IVM did not affect embryo development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system (CNS) tumor with a short survival time. The failure of chemotherapy is ascribed to the low transport of chemotherapeutics across the Blood Brain Tumor Barrier (BBTB) and poor penetration into tumor tissue. In order to overcome the two barriers, small nanoparticles with active targeted capability are urgently needed for GBM drug delivery. In this study, we proposed PEGylated Polyamidoamine (PAMAM) dendrimer nanoparticles conjugated with glioma homing peptides (Pep-1) as potential glioma targeting delivery system (Pep-PEG-PAMAM), where PEGylated PAMAM dendrimer nanoparticle was utilized as carrier due to its small size and perfect penetration into tumor and Pep-1 was used to overcome BBTB via interleukin 13 receptor α2 (IL-13Rα2) mediated endocytosis. The preliminary availability and safety of Pep-PEG-PAMAM as a nanocarrier for glioma was evaluated. In vitro results indicated that a significantly higher amount of Pep-PEG-PAMAM was endocytosed by U87 MG cells. In vivo fluorescence imaging of U87MG tumor-bearing mice confirmed that the fluorescence intensity at glioma site of targeted group was 2.02 folds higher than that of untargeted group (**p<0.01), and glioma distribution experiment further revealed that Pep-PEG-PAMAM exhibited a significantly enhanced accumulation and improved penetration at tumor site. In conclusion, Pep-1 modified PAMAM was a promising nanocarrier for targeted delivery of brain glioma., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A synergy between the polymer biomaterial and drug plays an important role in enhancing the therapeutic efficacy, improving the drug stability, and minimizing the local immune responses in the development of drug delivery systems. Particularly, in the case of ocular drug delivery, the need for the development of synergistic drug delivery system becomes more pronounced because of the wet ocular mucosal surface and highly innervated cornea, which elicit a strong inflammatory response to the instilled drug formulations. This article presents the development of a synergistic cysteamine delivery nanowafer to treat corneal cystinosis. Corneal cystinosis is a rare metabolic disease that causes the accumulation of cystine crystals in the cornea resulting in corneal opacity and loss of vision. It is treated with topical cysteamine (Cys) eye drops that need to be instilled 6-12 times a day throughout the patient's life, which causes side effects such as eye pain, redness, and ocular inflammation. As a result, compliance and treatment outcomes are severely compromised. To surmount these issues, we have developed a clinically translatable Cys nanowafer (Cys-NW) that can be simply applied on the eye with a fingertip. During the course of the drug release, Cys-NW slowly dissolves and fades away. The in vivo studies in cystinosin knockout mice demonstrated twice the therapeutic efficacy of Cys-NW containing 10 μg of Cys administered once a day, compared to 44 μg of Cys as topical eye drops administered twice a day. Furthermore, Cys-NW stabilizes Cys for up to four months at room temperature compared to topical Cys eye drops that need to be frozen or refrigerated and still remain active for only 1 week. The Cys-NW, because of its enhanced therapeutic efficacy, safety profile, and extended drug stability at room temperature, can be rapidly translated to the clinic for human trials.

Two human papillomavirus (HPV) viral oncoproteins, E6 and E7 represent ideal targets for development of a therapeutic HPV vaccine. It is important to reduce the rate of HPV-associated malignancies through improvement of vaccine modalities. In this study, we used a short amphipathic peptide carrier, Pep-1, for delivery of the full-length HPV16 E7 protein into mammalian cells and evaluated immune responses and protective effects of different formulations in C57BL/6 tumor mice model. Our results showed that the complexes of E7/Pep-1 protein form stable nanoparticles through noncovalent binding with an average size of 120 to 250 nm. The efficient delivery of E7 protein by Pep-1 at molar ratio of 1:20 was detected in HEK-293T cell line for 1 h and 3 h post-transfection. Immunization with E7/Pep-1 nanoparticles at a ratio of 1:20 induced a higher Th1 cellular immune response with the predominant IgG2a and IFN-γ levels than those induced by E7 protein in a murine tumor model. These data suggest that Pep-1 peptide would indicate promising applications for improvement of HPV therapeutic vaccines. © 2016 IUBMB Life, 68(6):459-467, 2016., (© 2016 International Union of Biochemistry and Molecular Biology.)

Background: The potential emergence and spread of resistance to artemisinins in the Plasmodium falciparum malaria parasite constitutes a major global health threat. Hence, improving the efficacy of artemisinins and of artemisinin-based combination therapy (ACT) represents a major short-term goal in the global fight against malaria. Mice defective in the enzyme pantetheinase (Vnn3) show increased susceptibility to blood-stage malaria (increased parasitaemia, reduced survival), and supplementation of Vnn3 mutants with the reaction product of pantetheinase, cysteamine, corrects in part the malaria-susceptibility phenotype of the mutants. Cysteamine (Cys) is a small, naturally occurring amino-thiol that has very low toxicity in vivo and is approved for clinical use in the life-long treatment of the kidney disorder nephropathic cystinosis., Methods: The ability of Cys to improve the anti-plasmodial activity of different clinically used artemisinins was tested. The effect of different CYS/ART combinations on malarial phenotypes (parasite blood-stage replication, overall and survival from lethal infection) was assessed in a series of in vivo experiments using Plasmodium strains that induce either blood-stage (Plasmodium chabaudi AS) or cerebral disease (Plasmodium berghei ANKA). This was also evaluated in an ex vivo experimental protocol that directly assesses the effect of such drug combinations on the viability of Plasmodium parasites, as measured by the ability of tested parasites to induce a productive infection in vivo in otherwise naïve animals., Results: Cys is found to potentiate the anti-plasmodial activity of artesunate, artemether, and arteether, towards the blood-stage malaria parasite P. chabaudi AS. Ex vivo experiments, indicate that potentiation of the anti-plasmodial activity of artemisinins by Cys is direct and does not require the presence of host factors. In addition, potentiation occurs at sub-optimal concentrations of artemisinins and Cys that on their own have little or no effect on parasite growth. Cys also dramatically enhances the efficacy and protective effect of artemisinins against cerebral malaria induced by infection with the P. berghei ANKA parasite., Conclusion: These findings indicate that inclusion of Cys in current formulations of ACT, or its use as adjunct therapy could improve the anti-plasmodial activity of artemisinin, decrease mortality in cerebral malaria patients, and prevent or delay the development and spread of artemisinin resistance.

Introduction: Calcium hydroxide (Ca[OH]2) is a widely used interappointment dressing, but its antibacterial property is compromised by dentin. Hence, the addition of chlorhexidine (CHX) with Ca(OH)2 has been proposed. However, the antimicrobial efficacy of this mixture compared with Ca(OH)2 alone is currently still debatable. Cysteamine is a mucolytic agent used to reduce the viscosity of mucus through the disruption of proteins, which are also important components of the extracellular matrix of biofilms. The aims of this study were to determine the efficacy of cysteamine alone and in combination with Ca(OH)2 to eradicate Enterococcus faecalis biofilm compared with CHX with Ca(OH)2, and to determine if this effect is affected by dentin., Methods: The biofilm eradication efficacies of Ca(OH)2 alone and with cysteamine were determined using 7-day E. faecalis biofilm cultured on dentin discs and compared with Ca(OH)2 with 2% CHX. The effects of dentin on the efficacies of Ca(OH)2 alone and with either cysteamine or CHX were examined., Results: Cysteamine alone completely abolished E. faecalis biofilm at 200 mg/mL. The combination of Ca(OH)2 with either cysteamine at 10 mg/mL or 2% CHX completely obliterated E. faecalis biofilm. Cysteamine with Ca(OH)2 completely eradicated E. faecalis biofilm despite preincubation with dentin, whereas CHX with Ca(OH)2 was less effective., Conclusions: Cysteamine effectively eliminated E. faecalis biofilm and showed synergistic effects in combination with Ca(OH)2, which were unaffected by dentin. Hence, our findings support the use of cysteamine as a potential adjunct to Ca(OH)2 as an interappointment dressing., (Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

To overcome the major disadvantages of cysteamine, the only registered treatment for the rare genetic disease cystinosis, nine prodrugs of γ-glutamyl-cysteamine (4) were synthesized for evaluation. Esterification of the thiol conferred oxidative stability, while sufficient lipophilicity for oral bioavailability was achieved by acylation of the α-carboxyl group of γ-glutamyl-cysteamine (4). Low cytotoxicity was observed in cultured HaCaT keratinocytes using the MTT assay, with EC50 values higher than or similar to that of cysteamine. Successful uptake of the esterified prodrugs and the subsequent release of cysteamine into cultured human proximal tubule epithelial cells were demonstrated using CMQT derivatisation and HPLC with UV detection. These prodrugs show potential as novel delivery vehicles of cysteamine to improve the treatment of the genetic disorder nephropathic cystinosis., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)